The proposed study is directed towards understanding the molecular mechanism of action of cannabinoids. It will seek to identify, within the cannabinoid structures, those molecular features required to produce the membrane perturbations that result in alterations of the cellular functions. The project will focus on a carefully selected group of cannabinoid analogs closely related in structure but covering a wide range of potencies, and will include detailed studies on: (a) the conformations of the cannabinoids in solution using high resolution NMR techniques; (b) the interactions of cannabinoids with representative phospholipid model membranes using 2H, 13C and 31P solid state NMR techniques (these studies will require the synthesis of specifically 2H and 13C labeled phospholipids as well as the synthesis of specifically 2H labeled cannabinoids); (c) the interactions of cannabinoids with a natural membrane (synaptosomal plasma membrane) using 2H solid state NMR techniques. The above findings will be correlated with the effects of cannabinoids on the uptake of biogenic amines (norepinephrine, dopamine, serotonin) aby brain synaptosomes.